Reveal The Structural Details Of The Protein A2aAR, Help To Develop Better Drugs

January 4, 2018 - A protein called the A2A adenosine receptor (A2aAR) is a member of the G-protein coupled receptor (GPCR) family. About 40% of all approved drugs are GPCRs.

All human cells contain A2aAR and other GPCRs that are embedded in the cell membrane. More than 800 GPCRs have been found in the human body, each of which has a role in regulating body functions. For example, A2aAR regulates blood flow and inflammation and mediates caffeine. A2aAR is a target for the treatment of Parkinson's disease and is also a relatively new target for the treatment of cancer.

In previous research, scientists used an imaging technique known as X-ray crystallography to determine the three-dimensional structure of A2aAR. These structures have shown that A2aAR looks like a chain that crosses over the cell membrane and has an opening on the extracellular side. The region of the GPCR that extends from the cell membrane interacts with the drug and other molecules, signaling the partner proteins in the cell.

Although the crystal structure provides a crucial profile for the shape of A2aARs in both the inactive and active state, they do not show that when this receptor encounters a new binding partner (such as a drug candidate), its Movement and structural changes. In short, one needs to study why and how A2aAR works.

To solve this problem, in a new study, researchers from the Scripps Institution in the United States used a technique called nuclear magnetic resonance spectroscopy (NMR) A2aAR in different conformations provides a new understanding of how it alters its shape on the surface of human cells in response to the drug. Relevant findings were published online in the Cell journal on December 28, 2017, and the paper was titled "Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor." The paper was written by Dr. Kurt Wüthrich, Professor of Structural Biology at Scripps Research Institute. The first author of the paper is Dr. Matthew Eddy of the Scripps Institution.

Image from Cell, doi: 10.1016 / j.cell.2017.12.004.

NMR produces a strong magnetic field that determines the probe's position in the sample. Using NMR, one can determine the structure of proteins and study their kinetic properties in solution at physiological temperatures-the way they exist in the human body.

Importantly, NMR allowed these researchers to visualize the changes in the internal structure of A2aAR. This goes beyond the previous solution NMR studies, as these previous studies focused on the gross observation of probes attached to flexible parts of GPCRs, mostly on or near the surface of such receptors. The methodology used in this new study allowed them to track the effect of drug binding to the extracellular domain of A2aAR on the structural and intracellular domain dynamics of this receptor.

Think again about how we design drugs

Two details in the A2aAR structure allow these researchers to create new insights into how future development of drugs might manipulate this receptor. A key finding is that the ability to replace a particular amino acid at this receptor center destroys its ability to send signals to cells.

These researchers also revealed a "toggle switch" activity in A2aAR. Previous studies have suggested that one tryptophan in A2aAR flips up and down depending on the activity of A2aAR. Using NMR, they directly observed this unique tryptophan, because it changed its orientation in response to different drugs. Chemists may potentially modify the drug to manipulate the switch and control the A2aAR signal.

These researchers stress that the new study may be related to the majority of members of the GPCR family. In fact, the structural details obtained in this study may apply to over 600 Class A GPCRs in our body.